Molecular Mechanisms of FLASH Radiotherapy in Alleviating Lung Normal Tissue Injury: Insights from Single-Cell...

Area of Science:

• Oncology
• Radiation Oncology
• Molecular Biology

Background:

• Conventional radiotherapy causes significant normal tissue toxicity.
• The molecular mechanisms underlying the protective "FLASH effect" of ultra-high dose rate radiotherapy (FLASH-RT) are not fully understood.
• Previous research suggests a role for mitochondrial homeostasis in normal cell protection during proton FLASH-RT.

Purpose of the Study:

• To elucidate the molecular mechanisms of FLASH-RT in normal lung tissue and orthotopic lung tumors.
• To compare the effects of FLASH-RT with conventional radiotherapy using a mouse model.
• To analyze single-cell gene expression profiles to understand differential cellular responses.

Main Methods:

• Orthotopic lung cancer mouse model.
• Comparison between FLASH-RT and conventional radiotherapy.
• Single-cell RNA sequencing (scRNA-seq) for gene expression analysis.

Main Results:

• FLASH-RT protects normal lung tissue by regulating the immune microenvironment, inhibiting oxidative stress, reducing apoptosis, and preserving mitochondrial function.
• Tumor cells exhibit differential responses including activated autophagy/apoptosis, enhanced stress responses, disrupted mitochondrial homeostasis, and PI3K/Akt pathway regulation leading to cell cycle arrest.
• FLASH-RT demonstrates distinct molecular effects on normal versus tumor tissues.

Conclusions:

• FLASH-RT offers normal tissue protection and tumor cytotoxicity through specific molecular mechanisms.
• Understanding these mechanisms provides a basis for clinical translation and advancing precision radiotherapy.
• The study highlights the potential of FLASH-RT for improved cancer treatment outcomes.